Antigenically diverse pathogens such as pneumococci present novel evolutionary challenges for vaccine design. The use of vaccines directed against variable antigens can cause, and has caused, increases in pathogen types not carrying the antigenic variants included in the vaccine. this evolutionary response of the population of streptococcus pneumonia (pneumococcus) to vaccine -induced selective pressure, known as "serotype replacement," may in turn cause a shift in patterns of disease. serotype replacement may be either beneficial or harmful, depending on the ability of the replacing types to cause disease. The research proposed here is to ascertain is designed to ascertain the biological mechanisms underlying the observed population biology of pneumococci in unvaccinated populations and to use this knowledge to predict how the population will respond when vaccines are widely used. Experimental models of pneumococcal carriage in mice and analysis of epidemiological data will be used to characterize the ecological mechanisms underlying pneumococcal diversity and population biology, and these mechanisms will be incorporated into a mathematical model of pneumococcal carriage and transmission. The predictions of this model will be using molecular epidemiological studies of pneumococcal isolates from community randomized trial of the pneumococcal conjugate vaccine. the specific aims are: 1) to characterize quantitatively the population- biological interactions between pneumococcal strains in a laboratory mouse model of intra nasal carriage. 2) to characterize the development of antibody-mediated immunity due to natural pneumococcal carriages and the impact of this immunity on dynamics of pneumococci, to use these models to identify the mechanisms underlying existing patterns of the transmission mathematical models by characterizing the changes in pneumococcal populations following vaccination, using molecular epidemiological typing methods.